Peripheral bacterial infections without impaired blood brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease(PD).Peripheral infection promotes innate immune training in microglia ...Peripheral bacterial infections without impaired blood brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease(PD).Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation.However,how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown.In this study,we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS.GSDMD in peripheral myeloid cells promoted microglial immune training,thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner.Furthermore,pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models.Collectively,these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD.Based on these findings,GSDMD may serve as a therapeutic target for patients with PD.展开更多
基金supported by the National Key R&D Program of China(2021ZD0202900 to Gang Hu,2022YFA1303900 to Shuo Yang and Chunmei Ma)National Natural Science Foundation of China(81991523 to Gang Hu and Bingwei Wang,32270921 and 82070567 to Shuo Yang,82270539 to Chunmei Ma,82104146 to Sheng Li)+3 种基金the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(2020YLXK017 to Bingwei Wang,China)the Open Project of State Key Laboratory of Neuroscience,Chinese Academy of Sciences(SKLN-202006 to Bingwei Wang,China)the Natural Science Foundation of Jiangsu Province(BK20221352 to Bingwei Wang,China)the Priority Academic Program Development of Jiangsu Higher Education Institutions(to Gang Hu and Bingwei Wang,China)。
文摘Peripheral bacterial infections without impaired blood brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease(PD).Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation.However,how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown.In this study,we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS.GSDMD in peripheral myeloid cells promoted microglial immune training,thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner.Furthermore,pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models.Collectively,these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD.Based on these findings,GSDMD may serve as a therapeutic target for patients with PD.
